DESCRIPTION OF THE RELATED ART
Ibuprofen, the chemical name of which is 2-(4-isobutylphenyl)propionic acid, is a well-known medicament with anti-inflammatory, antipyretic and analgesic activities. The uses of ibuprofen include the treatment of pain and inflammation in muscoskeletal disorders such as rheumatic disease and the treatment of pain in a variety of other disorders, for example headache, neuralgia and dysmenorrhoea.
Codeine, the chemical name of which is 7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol, is also a well-known medicament and has analgesic, narcotic, antispasmodic and antitussive activities.
On some occasions it is advantageous to provide a formulation containing a combination of ibuprofen and codeine, for example in the treatment of post-operative pain, dysmennorhoea, pain due to trauma, e.g. sprains, and post-extraction dental pain (see for example Cooper et al, Journal of Human Pharmacology and Drug Therapy, 1982, volume 2, number 3, p.162-167). It has been found however, that the storage properties of pharmaceutical compositions comprising an admixture of ibuprofen and codeine are generally unsatisfactory. This is most clearly seen in a tablet where, after a short period of time, the tablet presentation becomes unacceptable. This may take the form of discolouration, expansion or cracking of the tablet which may eventually lead to the break up of the tablet. Excipients which may be incorporated in typical dosage forms include one or more of binders, diluents, disintegrants, lubricants or stabilisers. The degree of discolouration, cracking or expansion may vary according to the choice and amounts of excipients used to form the composition. Some systems of excipients and active ingredients interact to a greater extent than others. It has been observed, for example that when well-known disintegrants such as cross-linked polyvinylpyrrolidones, croscarmellose sodium, maize starches, sodium starch glycollate and a commercially available mixture of 17% protein and 80% high molecular weight polysaccharide, sold under the trade name Emcosoy, are incorporated in solid compositions comprising ibuprofen and codeine, a satisfactory storage stability is not achieved. In particular, the appearance and form of a tablet containing ibuprofen, codeine and the above-mentioned disintegrants becomes unacceptable after a short period of time.
The problem of interaction is addressed in European Patent Application 159852, with particular emphasis on the problem of providing a satisfactory pharmaceutical composition containing codeine or its salts and other non-steroidal analgesics (including ibuprofen), as interaction causes discolouration of the product and adversely affects the stability of the active ingredients. A multi-stage process is disclosed in EP 159852A which minimises contact between the active ingredients in order to improve the stability of the resulting product. The process comprises
blending one of the active ingredients with a binder and a filler;
wet granulating the mixture so produced in the presence of a solvent;
drying the granulated mixture;
sizing the granulated mixture; and
blending the mixture with one or more other pharmaceutically active ingredients.